Genetic constraint at single amino acid resolution improves missense variant prioritisation and gene discovery
Genetic constraint at single amino acid resolution improves missense variant prioritisation and gene discovery
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单氨基酸分辨率的遗传约束改善了错义变异优先排序和基因发现
DOI：
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
J. Ware
中科院分区：
文献类型：
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作者：
Xiaolei Zhang;P. Theotokis;Nicholas Li;C. Wright;K. Samocha;N. Whiffin;J. Ware
大多数人类种系错义变异的临床影响尚不清楚。遗传约束确定负选择下的基因组区域，其中变异可能具有功能影响，但现有约束度量的空间分辨率有限。在这里，我们提出了同源错义约束（HMC）评分，它通过聚集蛋白质同源物的信号来测量准单氨基酸分辨率的遗传约束。我们在强负选择下鉴定出100万个可能的错义变体。HMC精确区分早期发病和成人发病疾病的致病性变异和良性变异。它优于现有的约束指标和致病性元预测因子，优先考虑来自发育障碍（DD）先证的新生突变，并且与这些正交，当联合使用时增加了功率。我们通过鉴定七个与DD相关的新基因来证明基因发现的实用性，这些基因可能通过功能改变机制起作用。总的来说，HMC是一种新的、强有力的预测因子，可以改善错义变异的解释。
The clinical impact of most germline missense variants in humans remains unknown. Genetic constraint identifies genomic regions under negative selection, where variations likely have functional impacts, but the spatial resolution of existing constraint metrics is limited. Here we present the Homologous Missense Constraint (HMC) score, which measures genetic constraint at quasi single amino-acid resolution by aggregating signals across protein homologues. We identify one million possible missense variants under strong negative selection. HMC precisely distinguishes pathogenic variants from benign variants for both early-onset and adult-onset disorders. It outperforms existing constraint metrics and pathogenicity meta-predictors in prioritising de novo mutations from probands with developmental disorders (DD), and is orthogonal to these, adding power when used in combination. We demonstrate utility for gene discovery by identifying seven genes newly-significant associated with DD that could act through an altered-function mechanism. Overall, HMC is a novel and strong predictor to improve missense variant interpretation.
DOI：
10.1056/nejmsr1406261
发表时间：
2015-06-04
期刊：
The New England journal of medicine
影响因子：
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作者：
Rehm HL;Berg JS;Brooks LD;Bustamante CD;Evans JP;Landrum MJ;Ledbetter DH;Maglott DR;Martin CL;Nussbaum RL;Plon SE;Ramos EM;Sherry ST;Watson MS;ClinGen
通讯作者：
ClinGen